Reduced Alcohol Consumption and Major Adverse Cardiovascular Events Among Individuals With Previously High Alcohol Consumption

This cohort study examines the association of reduced alcohol consumption with risk of major cardiovascular events among individuals who drink heavily.


Introduction
Alcohol consumption is one of the most prevalent behavioral factors in personal and public health.
[3][4]9 For example, the incidence of coronary artery disease (CAD) consistently decreased over a range of alcohol consumption (starting from >2.5 g/d); otherwise, U-or J-shaped dose-response patterns were observed for CVD mortality and stroke incidence. 11][12][13] Therefore, the association of alcohol consumption on future CVD should be investigated in the context of habitual change rather than fixed behavior.This methodological approach could provide practical evidence for clinicians who often encounter questions regarding the cardiovascular benefits of changing drinking behaviors.Notably, there is a lack of studies demonstrating the cardiovascular benefits of reduced alcohol consumption in people who drink heavily. 10,12Moreover, it is crucial to substantiate the result of behavioral changes in this population according to different CVD subtypes.
Herein, we hypothesized that habitual changes in alcohol consumption among individuals with sustained heavy drinking would have a long-term role in future CVD outcomes.We conducted a nationwide population-based cohort study to investigate the association between reduced alcohol consumption and risk of major adverse cardiovascular events (MACEs) in people who drink heavily across different CVD subtypes.

Study Data Source
This nationwide population-based cohort study used data from the Korean National Health Insurance Service-Health Screening (NHIS-HEALS) database.The institutional review board of Chungbuk National University Hospital approved this study and waived the informed consent requirement because anonymized data were used.We complied with the Declaration of Helsinki 14   were assessed by trained investigators using self-reported questionnaires.Details of the study data source have been published previously. 15The complete dataset, approved by the NHIS, was analyzed between February and May 2023.

Study Population
Figure 1 shows the flowchart of participant enrollment.Individuals who underwent the first medical checkup between 2005 and 2008 were included at baseline.The prespecified exclusion criteria are shown in Figure 1.Participants who abstained from alcohol drinking during the second checkup period were excluded, as the presence of the sick-quitter effect could confound the outcomes of alcohol-related behavioral change. 13Self-reported questionnaires were used to assess alcohol consumption amounts in participants who underwent health examinations over 2 consecutive periods (first period: 2005-2008; second period: 2009-2012).
eTable 1 in Supplement 1 shows the alcohol consumption calculation process.The risk level of alcohol consumption was defined using the mean intake amount during each health examination period according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria, as previously described. 16,17Based on the NIAAA criteria, heavy drinking was defined as more than 4 drinks (56 g) per day or more than 14 drinks (196 g) per week for males and more than 3 drinks (42 g) per day or more than 7 drinks (98 g) per week for females (eTable 2 in Supplement 1).All study participants exhibited heavy drinking during the first health examination period (2005-2008) and

Study Outcomes
The primary outcome was the occurrence of MACEs until December 31, 2019.Defined as a composite outcome, MACEs included nonfatal myocardial infarction (MI) or angina requiring revascularization, any stroke accompanied by hospitalization, and all-cause death with corresponding ICD-10 codes and death records.Procedure codes for coronary revascularization, including both interventional and surgical therapies, were incorporated to enhance the diagnostic accuracy of clinically relevant CAD. 18,19condary outcomes consisted of each component of the primary MACE composite.The index date of follow-up was the last screening date in the second health examination period.The study end date was the date that 1 of the following events occurred: (1) development of a cardiovascular outcome episode, (2) death, or (3) latest hospital visit of participants who remained free of outcome events.The first year following the end of the second health examination period up to December 31, 2013, was established as the washout period to minimize the potential lag of heavy alcohol consumption (mean [SD] washout duration, 23.0 [9.9] months).

Statistical Analysis
Summary statistics were expressed as mean (SD) or number (%).The differences among groups were evaluated using an unpaired, 2-tailed t test for continuous variables and χ 2 test for categorical variables.To minimize the implications of potential confounders, propensity score matching (PSM) analysis was performed using a logistic regression model with the nearest-neighbor method.The propensity score was calculated including potential confounders within the baseline covariates (eMethods in Supplement 1).The maximum absolute standardized difference was calculated, and values less than 0.1 indicated a negligible difference.The crude incidence rate was calculated as the number of events per 100 000 person-years.Cumulative incidence curves for MACEs were generated using the Kaplan-Meier method with the log-rank test.Hazard ratios (HRs) and 95% CIs of the study end points were estimated using multivariate Cox proportional hazards regression models.
Subgroup analyses were conducted for MACEs using the following variables: age, sex, BMI, physical activity level, income status, medical comorbidities, modified CCI, and washout duration.Sensitivity analysis was performed using an alternative PSM and excluding measurement variables potentially modifiable by changes in alcohol consumption.
All statistical analyses were performed using RStudio, version 4.3.1 (R Project for Statistical Computing).All P values were 2-tailed, and P < .05indicated statistical significance.

Baseline Characteristics and Laboratory Findings
Among the 21 011 included participants with heavy alcohol consumption at baseline (18   1 and Figure 1).

Main Outcomes
Over the follow-up duration of 162 378 person-years, 899 participants (6.3%) in the sustained heavy drinking group and 354 (5.2%) in the reduced drinking group developed MACEs.Figure 2 shows the Kaplan-Meier survival curve of the cumulative MACE incidence according to changes in alcohol consumption after PSM.The sustained heavy drinking group showed a significantly higher incidence of MACEs than the reduced drinking group (log-rank P < .001).The Kaplan-Meier curve of cumulative MACE incidence started to diverge after 3 years, and the difference gradually increased over time.

Subgroup Analysis
Figure 3 shows the results of the subgroup analysis.While nonsignificant interactions were observed except for prior heart failure (HF) (P for interaction = .04),the prevention of MACEs associated with transitioning to reduced drinking was prominent in the subgroups of males (PSM HR, 0. and CKD (PSM HR, 0.75; 95% CI, 0.65-0.86).Notably, the cardiovascular benefits of alcohol reduction were consistently observed regardless of modified CCI; income status; and certain medical conditions, including hypertension, diabetes, dyslipidemia, and HF.Additionally, no definite interaction was observed concerning the washout duration (eTable 3 in Supplement 1).

Sensitivity Analysis With Alternative PSM
Additional PSM analysis was conducted by excluding variables potentially modifiable by changes in alcohol consumption (eTable 4 and eResults in Supplement 1).These findings did not alter the observed cardiovascular benefits associated with reduced alcohol consumption.

Discussion
In this nationwide population-based cohort study, reduced alcohol consumption among people who drink heavily was associated with a lower risk of future cardiovascular events.Notably, habitual changes in heavy alcohol consumption from 2009 to 2012 were beneficial over the subsequent follow-up period of up to 10 years.Moreover, these benefits became increasingly evident approximately 3 years after the initiation of alcohol-related behavioral change.These preventive attributes were consistently observed across the various subgroups of people who drank heavily.The cardiovascular benefits of reduced alcohol intake presented differentially according to subtypes of CVD.More pronounced benefits were found, such as lower risk of ischemic stroke and ischemiadriven revascularization for angina.Collectively, these findings suggest that reducing alcohol consumption among people who drink heavily is potentially associated with a broad spectrum of benefits in future cardiovascular events and specific CVD subtypes.

Biological Mechanism of Protection From Reduced Alcohol Intake
Many previous studies have reported a potential association between mild to moderate alcohol consumption and reduced cardiovascular risk; however, a causal association remains unclear.Several plausible biological mechanisms have been proposed to explain this phenomenon.Mild to moderate alcohol consumption orchestrates various biological processes that mitigate cardiovascular risk, including beneficial regulation of lipid profiles and fibrinolysis, 20 decreased platelet aggregation, 21 improved endothelial dysfunction, 22 reduced vascular inflammation, 23 and insulin resistance. 24rthermore, mild to moderate alcohol consumption can play a role in lower stress-associated neurobiological activity, 25 a neural underpinning of atherosclerotic CVD. 26,27These biological mechanisms of mild to moderate alcohol consumption may collaborate synergistically to reduce the risk of future CVD.In contrast, heavy alcohol consumption is associated with increased future cardiovascular risk by promoting predisposing medical comorbidities, including hypertension, obesity, and sleep apnea.Based on this evidence, it can be hypothesized that reducing alcohol intake among people who drink heavily may be a factor in lower future cardiovascular risks.While this hypothesis remains to be thoroughly examined, conducting a large-scale prospective randomized clinical trial is nearly impossible because of ethical concerns regarding the establishment of individuals with sustained heavy drinking as the control group.Given these constraints, this cohort study provides crucial evidence regarding this high-risk population.

Differential Implications for Coronary Vascular and Cerebrovascular Beds
Although mild to moderate alcohol consumption is generally considered to be protective against CAD, 1,3,4,8,9,28 it remains unclear whether comparable benefits are expected from habitual changes in people who drink heavily.The present study found that reducing alcohol consumption in people who drink heavily is associated with lower risk of future CAD.This study introduced a novel perspective by conceptualizing alcohol consumption as a dynamic behavior and enables the exploration of the clinical implications of alcohol-related behavioral changes.The key findings align with contemporary guidelines, supporting the potential benefit of mild to moderate alcohol consumption in CAD. 29,30Reduced alcohol consumption in individuals who drink heavily was associated with a 29% decrease in the overall risk of CAD (PSM HR, 0.71; 95% CI, 0.52-0.98),which was mostly accounted for by a decrease in stable or unstable angina.The benefit of mild to moderate alcohol consumption in participants with CAD appeared to be less prominent in MI occurrence.This discrepancy between angina and MI has been documented in previous studies. 2,4Although the detailed pathophysiological mechanisms remain to be clarified, the present study highlighted the divergent outcomes of reduced alcohol consumption across distinct subtypes of CAD.The potential neuroprotection of mild to moderate alcohol consumption has been reported based on a U-shaped or curvilinear dose-response relationship for the incidence or mortality of stroke. 1,3,4,9However, no studies have addressed the implications of alcohol-related behavioral changes in heavy drinking across different stroke subtypes.In the present study, we conducted a dedicated analysis to explore the differential benefits of less alcohol intake by individual stroke subtypes.Reduced alcohol consumption in individuals who drank heavily resulted in a 34% decrease in risk of ischemic stroke (PSM HR, 0.66; 95% CI, 0.51-0.86);however, this preventive association did not correspond to hemorrhagic stroke.Theoretically, this discrepancy may be attributed to the altered platelet function and coagulation factors following moderate alcohol consumption that leads to higher susceptibility to hemorrhagic stroke. 31The findings from the present study are congruous with those of previous studies that reported on the differential association between alcohol consumption and distinct stroke types. 32,33Additionally, a previous study demonstrated that reduced drinking was associated with lower risk of AF. 34 Taken together, these findings suggest a potential to reduce ischemic events but a neutral or inverse association with hemorrhagic events.
Another important aspect to consider is that ischemic stroke is a multifactorial and heterogeneous disease.Given its intricate pathophysiological processes, a substantial knowledge gap persists concerning the divergent implications of mild to moderate alcohol consumption according to different subtypes of ischemic stroke.Future studies should clarify these issues to enhance the understanding of the cerebrovascular implications of alcohol-reduction interventions.

Strengths and Limitations
This study has some strengths.To our knowledge, this study was the first to demonstrate the clinical implications of habitual changes in alcohol consumption among people who drink heavily for the future risk of cardiovascular events.Reduced alcohol consumption in individuals with sustained heavy drinking was associated with lower incidence of angina and ischemic stroke.These findings provide practical insights into the development of diagnostic and therapeutic strategies to effectively manage heavy drinking in routine clinical practice.Clinicians may be apprehensive about the substantially higher risk of angina or ischemic stroke in people who drink heavily.Furthermore, clinicians can offer personalized guidance to reduce alcohol consumption and effectively manage specific subtypes of alcohol-attributable CVDs.
This study has certain limitations.First, assessment that uses self-reported alcohol intake has the potential to result in misclassification.Second, we were unable to detect additional alcoholrelated behavioral changes before the first health examination period and beyond the second health examination period.We assumed that the alcohol consumption captured during the second health examination period remained unchanged during the follow-up.Third, the study population was composed exclusively of South Koreans.Future studies should include diverse ethnicities to establish global evidence and ascertain the generalizability of the findings.Fourth, the study design did not allow for the identification of a causal association.While a randomized clinical trial is precluded by ethical concerns, the time-exposure study design provided the opportunity to explore potential biological associations.Fifth, we were unable to assess individual variations in alcohol metabolism, such as single-nucleotide variants (formerly single-nucleotide polymorphisms).Sixth, detailed information on the cause of death and broader socioeconomic status was unavailable in the NHIS-HEALS database.Seventh, despite conducting a PSM analysis, it remains possible that residual confounding factors might have been included in the analysis.Eighth, the study design might not inherently exclude survivor bias.However, examining 2 distinct health examination periods is crucial to investigate changes in lifestyle behavior, such as alcohol consumption, and results should be interpreted with consideration of this aspect.Nine, absolute abstinence from heavy alcohol consumption was not thoroughly evaluated due to the limited sample size and event number of abstainers.
and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.The overall population cohort consisted of a random sample representing 10% of Korean residents with national health insurance coverage aged 40 to 79 years on December 31, 2002, who were also included in the 2002 to 2003 National Health Screening Program (NHSP).Given that the NHSP is a mandatory program that encompasses approximately 97.1% of adults, this cohort was JAMA Network Open | Cardiology

Figure 1 .
Figure 1.Flowchart of the Study Population 514 866 Individuals identified from the NHIS-HEALS database

Figure 3 .
Figure 3. Subgroup Analysis of the Risk of Major Adverse Cardiovascular Events Between Reduced Drinking vs Sustained Heavy Drinking Groups Risk of Adverse Cardiovascular Events in Individuals With Heavy Alcohol Use Who Reduce Their Consumption JAMA Network Open.2024;7(3):e244013.doi:10.1001/jamanetworkopen.2024.4013(Reprinted) March 28, 2024 2/13 Downloaded from jamanetwork.comby guest on 03/31/2024 representative of the entire adult population in South Korea.The variables contained in the NHIS-HEALS database included demographic characteristics, disease codes, prescription records, income status, and mortality information.Personal records of blood pressure readings, anthropometric measurements, medical and family histories, lifestyle behaviors, and laboratory results were systematically collected using the NHSP.Lifestyle behavioral factors, including alcohol consumption,

be excluded for multiple reasons. JAMA Network Open | Cardiology Risk
of Adverse Cardiovascular Events in Individuals With Heavy Alcohol Use Who Reduce Their Consumption a Individuals could

Table 1
heavy drinking group consisted of a greater proportion of individuals with current smoking, obesity, and high-income status.Conversely, the reduced drinking group had a higher incidence of CKD (7.2% vs 6.1%; P = .002)andelevatedmean (SD) LDL-C levels (116.21[35.81]vs 113.30[35.56] mg/dL; P < .001; to convert to millimoles per liter, multiply by 0.0259) than the sustained heavy drinking group.After PSM, all variables were well balanced between the groups except for age, sex, and hemoglobin level.The maximum absolute standardized difference remained below 0.1 for all variables except for sex.

Table 2 .
Hazard Ratios (HRs) for Primary and Secondary Outcomes by Group Adjusted for age, sex, body mass index, obesity, systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, hemoglobin, glucose, serum creatinine, alanine aminotransferase, smoking status, physical activity, hypertension, diabetes, dyslipidemia, heart failure, chronic kidney disease, atrial fibrillation, modified Charlson Comorbidity Index, and income status.
a The HRs were calculated using multivariate Cox proportional hazards regression models before and after PSM.b Potential Confounding Variables Included in the PSM Analysis eResults.Sensitivity Analysis With Alternative PSM eTable 1. Overall Process of Alcohol Consumption Calculation eTable 2. Operational Definitions of Alcohol Consumption Levels, Confounding Variables and Primary Outcome eTable 3. Subgroup Analysis of MACEs Risk Between Reduced Drinking and Sustained Heavy Drinking Stratified by Washout Duration eTable 4. Adjusted Hazards Ratios for Primary and Secondary Outcomes in Alternative PSM Analysis Excluding